Reverse cholesterol transport
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Reverse cholesterol transport (RCT) is a multistep process comprising removal of excess cholesterol from cells in the body and delivery to the liver for excretion into the small intestine. [1]
Enhancing reverse cholesterol transport is considered a potential strategy for preventing and treating atherosclerosis and associated diseases such as cardiovascular disease and stroke.[2] Atherosclerosis is caused by the build-up in arterial blood vessels of atherosclerotic plaques. These consist mostly of foam cells, which are macrophages overloaded with cholesterol and other lipids. Foam cells and other cells in peripheral tissues can hand over their excess cholesterol to high-density lipoprotein (HDL) particles. These will transport the cholesterol via the lymph and then the blood stream to the liver, from where it will be excreted with bile into the small intestine. Reverse cholesterol transport thereby works against the build-up of atherosclerotic plaques from dying foam cells.
In more detail, reverse cholesterol transport proceeds in the following steps:
- Formation of nascent HDL: The liver and intestines produce nascent, cholesterol-free high-density lipoprotein (HDL) particles, primarily composed of Apolipoprotein A1 (ApoA-1).
- Cholesterol efflux from peripheral cells: Peripheral cells, including macrophage-derived foam cells, excrete excess cholesterol through their plasma membrane, via ABCA1 (ATP-binding cassette transporter) and ABCG1 transporter proteins. Nascent HDL particles, bound on the outside of the cells to ABCA1 and ABCG1, take up the cholesterol.[3] The HDL particles then get transported with the interstitial fluid (the fluid between cells) to the lymphatic system and from there to the bloodstream.
- Esterification of cholesterol: Within HDL particles, the enzyme lecithin-cholesterol acyltransferase (LCAT) esterifies free cholesterol into cholesteryl esters, which migrate to the core of the HDL particle, transforming it into a mature, spherical form.
- Direct hepatic uptake: The mature HDL in the blood can deliver cholesteryl esters directly to the liver through interactions with hepatic receptors such as scavenger receptor class B type I (SR-BI).[4]
- Alternate route by cholesteryl ester transfer: Cholesterylester transfer protein (CETP) facilitates the exchange of cholesteryl esters in HDL with tryglycerides in ApoB-containing lipoprotein particles (LDL, VLDL, IDL). These lipoprotein particles can then deliver cholesterol to the liver via its LDL receptors. (These particles are mostly responsible to transport cholesterol from the liver to peripheral cells, as part of the normal, "non-reverse" direction of cholesterol transport.)
- Excretion of cholesterol: The liver converts the excess cholesterol into bile acids or secretes it directly into bile, which is then excreted into the small intestine. A portion of this cholesterol is eliminated from the body via feces, completing the RCT process.
Through these steps, RCT plays a vital role in maintaining cholesterol homeostasis and preventing the accumulation of cholesterol in peripheral tissues, thereby reducing the risk of cardiovascular diseases.
While excess fat (lipids) can simply be catabolized (burned) by cells as energy source, cholesterol's complex molecular structure cannot be efficiently catabolized. Therefore, excess peripheral cholesterol is recycled to the liver via RCT.
Adiponectin induces ABCA1-mediated reverse cholesterol transport from macrophages by activation of PPAR-γ and LXRα/β.[5]